Methods of preparing pharmaceutical compositions comprising eslicarbazepine acetate and methods of use

ABSTRACT

The present disclosure relates to the treatment of various diseases and conditions with eslicarbazepine acetate. The present disclosure also relates to the use of eslicarbazepine acetate in a method for reducing or decreasing epileptic seizures in a patient. The present disclosure also relates to a method for increasing the exposure to eslicarbazepine in a patient. The present disclosure also relates to a method of preparing a pharmaceutical composition comprising eslicarbazepine acetate.

This is a continuation of U.S. patent application Ser. No. 13/017,732,filed Jan. 31, 2011, which is a continuation of U.S. patent applicationSer. No. 11/123,205, filed May 6, 2005, both of which are incorporatedherein by reference.

BACKGROUND

The present disclosure relates to a pharmaceutical composition and atreatment method using eslicarbazepine acetate.

Epilepsy, pain conditions such as trigeminal neuralgia, and affectivebrain disorders such as bipolar disorder are commonly treated withcarbamazepine. Treatment with carbamazepine, however, can lead toserious side effects due to the production of toxic metabolites.Oxcarbazepine was developed to reduce the severity of those sideeffects, but oxcarbazepine has a greatly reduced potency. See, e.g.,Almeida, L. & Soares-da-Silva, P., “Safety, Tolerability, andPharmacokinetic Profile of BIA 2-093, a Novel Putative Antiepileptic, ina Rising Multiple-Dose Study in Young Healthy Humans,” J. Clin.Pharmacol., 44, 906-918 (2004) (herein referred to as “Almeida I”).

Thus, there is a need for a pharmaceutical composition and method fortreating various conditions or diseases such as, for example, epilepsy,trigeminal neuralgia, and affective brain disorders, that has a highpotency and a low occurrence of side effects.

SUMMARY

Eslicarbazepine acetate,(S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide(“BIA 2-093”), is a new drug currently being developed which is usefulfor the treatment of various conditions, such as, for example, epilepsyand affective brain disorders, as well as pain conditions and nervousfunction alterations in degenerative and post-ischemic diseases.Although chemically related to carbamazepine and oxcarbazepine,eslicarbazepine acetate is believed to avoid the production of certaintoxic metabolites (such as, for example, epoxides) and to avoid theunnecessary production of enantiomers or diastereoisomers of metabolitesand conjugates, without losing pharmacological activity. See Benes etal., “Anticonvulsant and Sodium Channel-Blocking Properties of Novel10,11-Dihydro-5H-dibenz[b,f]azepine-5-carboxamide Derivatives,” J. Med.Chem., 42, 2582-2587 (1999).

Like carbamazepine and oxcarbazepine, eslicarbazepine acetate isbelieved to be a voltage-gated sodium channel (VGSC) blocker thatcompetitively interacts with site 2 of the inactivated state of thesodium channel. The affinity for this state of the channel is similar tothat of carbamazepine, while the affinity for the resting state of thechannel is about 3-fold lower than that of carbamazepine. This profilemay suggest an enhanced inhibitory selectivity of eslicarbazepineacetate for rapidly firing neurons over those displaying normalactivity. See Bonifacio et al., “Interaction of the NovelAnticonvulsant, BIA 2-093, with Voltage-Gated Sodium Channels:Comparison with Carbamazepine,” Epilepsia, 42, 600-608 (2001).

Evaluation of the metabolic profile of eslicarbazepine acetate,following chiral analysis, in liver microsomes from rats, dogs, monkeysand humans was found to give the S(+) enantiomer of licarbazepine,(S)-(+)-10,11-dihydro-10-hydroxy-5H dibenz/b,f/azepine-5-carboxamide(also known as “eslicarbazepine”), and not the R(−) form oflicarbazepine, (R)-(−)-10,11-dihydro-10-hydroxy-5Hdibenz/b,f/azepine-5-carboxamide (also known as “R-licarbazepine”).

Studies in humans have shown that, after oral administration,eslicarbazepine acetate appears to be rapidly and extensivelymetabolized to the active metabolite eslicarbazepine and, in a minorextent, to R-licarbazepine. See Silveira et al., “BIA 2-093Pharmacokinetics in Healthy Elderly Subjects,” Epilepsia, 45 (suppl. 3),157 (2004). For example, the plasma concentrations of the parent drug(eslicarbazepine acetate) have been systematically found below the limitof quantification (LOQ) of the assay (10 ng/mL). See Almeida I; Almeida,L. & Soares-da-Silva, P., “Safety, Tolerability and PharmacokineticProfile of BIA 2-093, a Novel Putative Antiepileptic Agent, during FirstAdministration to Humans,” Drugs R&D, 4, 269-284 (2003) (herein referredto as “Almeida II”). When a non-chiral method is used, the assay doesnot distinguish between eslicarbazepine and the R-enantiomer, and themixture was reported as “BIA 2-005” or “racemic licarbazepine.”

The inventors performed entry-into-man studies in healthy subjects, theresults of which they described in the Almeida I and Almeida IIarticles, both of which are hereby incorporated by reference. In thesestudies, the healthy subjects received a single oral dose ofeslicarbazepine acetate wherein the dose ranged from 20 mg to 1200 mg(see Almeida II), and multiple daily-doses of eslicarbazepine acetateranging from 200 mg twice-daily to 1200 mg once-daily (see Almeida I).Further studies (not yet published) by the inventors have investigatedhigher doses of eslicarbazepine acetate, including, for example, dosesranging up to 2400 mg once-daily. The studies showed that BIA 2-005maximum observed plasma concentration (C_(max)) was attained at about 1hour to about 4 hours post-dose (t_(max)), the extent of systemicexposure to BIA 2-005 was approximately dose-proportional, andsteady-state of BIA 2-005 plasma concentrations was attained at about 4to 5 days. The mean renal clearance of BIA 2-005 from plasma was about20-30 mL/min, and the total amount of BIA 2-005 recovered in the urinewas approximately 20% and 40% within 12 hours and 24 hours post-dose,respectively.

The studies also showed that the apparent terminal half-life of BIA2-005 ranged from about 8 hours to about 17 hours. See, e.g., AlmeidaII.

U.S. Pat. No. 6,296,873 discloses a sustained release delivery systemfor carbamazepine, which has a half-life ranging from 25 hours to 85hours. To avoid adverse effects, U.S. Pat. No. 6,296,873 teaches thatthe carbamazepine should be administered in tablet form up to two ormore times daily to slowly release the compound to maintainconcentration levels between 4-12 μg/mL. Such a delivery system requiresa form that is capable of delivering the compound over an extendedperiod of time, such as a tablet form.

In one aspect of the present disclosure, the inventors have unexpectedlydiscovered an enhanced efficacy of eslicarbazepine acetate in thetreatment of various conditions, such as, for example, the treatment ofepilepsy, using once-daily administration compared to twice-dailyadministration. This discovery is particularly surprising because theapparent half-life of eslicarbazepine acetate (t_(1/2)=about 8 hours toabout 17 hours) is significantly shorter than the half-life ofcarbamazepine (t_(1/2)=25 hours to 85 hours), a compound typicallyadministered 3-4 times daily.

In another aspect of the present disclosure, the inventors have alsounexpectedly discovered an enhanced exposure to eslicarbazepine afteronce-daily administration of eslicarbazepine acetate versus thetwice-daily regimen in humans. Once-daily administration ofeslicarbazepine acetate surprisingly provides an increase of exposure toeslicarbazepine than the same drug dosage divided into twice-dailydoses.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Percentage reduction in seizure number in each dose periodversus baseline (400 mg once-daily versus twice-daily and placebo; 800mg once-daily versus twice-daily and placebo; 1200 mg once-daily versustwice-daily and placebo).

FIG. 2: Mean (95% Cl) trough plasma concentrations (μg/mL) of BIA 2-005following a daily dose of 400 mg, 800 mg and 1200 mg of BIA-2-093administered once-daily (o.d.) or twice-daily (b.i.d.).

DETAILED DESCRIPTION

The foregoing and following aspects and embodiments, including thestudies discussed herein, are described and illustrated in a mannerintending to be exemplary only, and should not be construed as limitingin scope.

One aspect of the present disclosure relates to a method for treating atleast one disease or condition in a patient in need thereof byadministering a pharmaceutical composition comprising eslicarbazepineacetate in a pharmacologically effective amount.

In one exemplary embodiment of the present disclosure, thepharmaceutical composition comprising eslicarbazepine acetate isadministered in a once-daily dosing regimen.

In another exemplary embodiment of the present disclosure, thepharmaceutical composition is administered in a dosage intended tomaximize the total exposure to eslicarbazepine, as measured by the rateof exposure and extent of exposure (C_(max) and AUC_(O-τ)).

In an exemplary embodiment of the present disclosure, the at least onedisease or condition treated may be chosen from, for example, epilepsy,central and peripheric nervous system disorders, affective disorders,schizoaffective disorders, bipolar disorders, attention disorders,anxiety disorders, neuropathic pain and neurophratic pain-relateddisorders, sensorimotor disorders, vestibular disorders, and nervousfunction alterations in degenerative and post-ischemic diseases.

Examples of affective disorders include depression, pre-menstrualdysphoric disorder, post-partum depression, post-menopausal depression,anorexia nervosa, bulimia nervosa, and neurodegeneration-relateddepressive symptoms.

The methods disclosed in the present disclosure may be used to treatschizoaffective disorders such as, for example, schizodepressivesyndromes, schizophrenia, extreme psychotic states, schizomanicsyndromes, dysphoric and aggressive behavior, episodic dyscontrol orintermittent explosive disorder, and borderline personality disorder.

Bipolar disorders that may be treated according to the methods of thepresent disclosure include, for example, bipolar disorder and unstablebipolar disorder with rapid fluctuations (rapid cyclers),manic-depressive disorders, acute mania, mood episodes, and manic andhypomanic episodes

Examples of attention disorders include attention deficit hyperactivitydisorders and other attention disorders, such as, for example, autism.

Anxiety disorders may include conditions such as, for example, socialanxiety disorders, post traumatic stress disorder, panic,obsessive-compulsive disorder, alcoholism, drug withdrawal syndromes,and cravings.

The neuropathic pain and neurophratic pain-related disorders that may betreated according to the methods of the present disclosure include, byway of example, neuropathic pain and associated hyperalgesia, includingtrigeminal, herpetic, post-herpetic and tabetic neuralgia, diabeticneuropathic pain, migraines, tension-type headaches, causalgia, anddeafferentation syndromes such as, for example, brachial plexusavulsion.

Examples of sensorimotor disorders include Restless legs syndrome,spasticity, hemifacial spasm, nocturnal paroxysmal dystonia, brainischemia associated motor and sensitive deficits, Parkinson's diseaseand parkinsonian disorders, antipsychotic-induced motor deficits,tardive dyskinesia, episodic nocturnal wandering, and myotonia.

Exemplary vestibular disorders include Tinnitus or other innerear/cochlear excitability related diseases, such as, for example,neuronal loss, hearing loss, sudden deafness, vertigo, and Meniere'sdisease.

In other exemplary embodiments, the at least one disease or conditionmay be chosen from epilepsy, bipolar disorder, and trigeminal neuralgia.In yet another embodiment, the disease may be refractory partialepilepsy.

One skilled in the art will understand that these conditions areexemplary only, and will understand from the disclosure what otherdiseases and conditions would be considered to be within the scope ofthe present disclosure.

Another aspect of the present disclosure relates to a pharmaceuticalcomposition comprising eslicarbazepine acetate and at least onepharmaceutical excipient, at least one auxiliary substance, at least onecarrier material, or combinations thereof.

A further aspect of the present disclosure relates to a method ofpreparing a pharmaceutical composition comprising combiningeslicarbazepine acetate with at least one excipient, at least oneauxiliary substance, at least one carrier material, or combinationsthereof. Suitable excipients, carrier materials, and other auxiliarysubstances which would be useful in the present invention are known tothose skilled in the art, and would be readily determined. Methods forpreparing pharmaceutical compositions are also known to those skilled inthe art.

In one exemplary embodiment of the present disclosure, thepharmaceutical composition may be in tablet form and may comprise atleast one excipient, auxiliary substance, and/or carrier material. Theat least one excipient, auxiliary substance, and/or carrier material maybe chosen from, for example, povidone, croscarmellose sodium, magnesiumstearate, saccharin sodium, dibasic calcium phosphate dihydrate, sodiumlauryl sulphate, flavorings, and combinations thereof. Exemplary tabletsmay be formed using granulation liquids, such as, for example, purifiedwater and ethanol.

In another exemplary embodiment of the present disclosure, thepharmaceutical composition may be in oral suspension form and maycomprise at least one excipient, auxiliary substance, and/or carriermaterial. The at least one excipient, auxiliary substance, and/orcarrier material may be chosen from, for example, xantham gum, macrogolstearate (such as, for example, Myrj 59 P, produced by UNIQEMA),methylparaben, propylparaben, saccharin sodium, sorbitol, buffers,flavorings, and combinations thereof.

Another aspect of the present disclosure relates to a method forreducing or decreasing the number, duration, or frequency of epilepticseizures in a patient by administering to the patient a dose of apharmaceutical composition comprising eslicarbazepine acetate in apharmacologically effective amount. In one exemplary embodiment of thepresent disclosure, the method for reducing epileptic seizures inpatients comprises administering a once-daily dose of the pharmaceuticalcomposition comprising a pharmacologically effective amount ofeslicarbazepine acetate.

The present disclosure also relates to a method for increasing theexposure to eslicarbazepine in a patient by administering to the patienta pharmaceutical composition comprising eslicarbazepine acetate in anamount effective to increase the plasma concentration of eslicarbazepineover the dosage interval. In one exemplary embodiment, the exposure toeslicarbazepine may be increased by delivering the pharmaceuticalcomposition in a manner that minimizes the number of daily doses. In afurther exemplary embodiment of the present disclosure, the method forincreasing the exposure to eslicarbazepine in the patient comprisesadministering to a patient a once-daily dose of a pharmaceuticalcomposition comprising an amount of eslicarbazepine acetate effective toincrease the plasma concentration of eslicarbazepine over the dosageinterval.

In a further exemplary embodiment of the present disclosure, the activeingredient of the pharmaceutical composition may consist essentially ofeslicarbazepine acetate.

In a further aspect of the present disclosure, eslicarbazepine acetatemay be administered to a patient in an amount resulting in a maximumplasma concentration (C_(max)) of eslicarbzepine greater than about7,400 ng/mL. In other exemplary embodiments, eslicarbazepine acetate maybe administered to a patient in an amount resulting in a C_(max) ofeslicarbazepine greater than about 12,000 ng/mL or greater than about16,100 ng/mL. In further exemplary embodiments, eslicarbazepine acetatemay be administered to a patient in an amount resulting in a C_(max) ofeslicarbazepine greater than about 22,700 ng/mL, such as greater thanabout 36,500 ng/ml, greater than about 45,200 ng/mL, or more.

In a further exemplary embodiment, eslicarbazepine acetate may beadministered to a patient in an amount resulting in a maximum plasmaconcentration (C_(max)) of eslicarbzepine up to about 58,800 ng/mL or upto about 67,800 ng/mL. In a further exemplary embodiment,eslicarbazepine acetate may be administered to a patient in an amountresulting in an area under the concentration curve (which corresponds tothe extent of systemic exposure) over the dosing interval (AUC_(0-τ)) ofeslicarbzepine up to about 885,000 ng·h/mL or up to about 1,000,000ng·h/mL.

For example, a once-daily dose of about 400 mg may be administered to apatient resulting in a maximum plasma concentration (C_(max)) ofeslicarbazepine greater than about 7,400 ng/mL. As a further example, aonce-daily dose of about 800 mg or about 1200 mg may be administered toa patient resulting in a C_(max) of eslicarbazepine greater than about16,100 ng/mL or greater than about 22,700 ng/mL, respectively. In otherexamples, eslicarbazepine acetate may be administered in a once-dailydose greater than about 1200 mg, such as about 1800 mg or about 2400 mg,to result in a C_(max) of eslicarbazepine greater than about 36,500ng/mL, about 45,200 ng/mL, respectively.

In a further aspect of the present disclosure, eslicarbazepine acetatemay be administered to a patient in an amount resulting in an area underthe concentration curve (which corresponds to the extent of systemicexposure) over the dosing interval (AUC_(0-τ)) of eslicarbazepinegreater than about 110,000 ng·h/mL. In other exemplary embodiments,eslicarbazepine acetate may be administered to a patient in an amountresulting in an AUC_(0-τ) of eslicarbazepine greater than about 240,000ng·h/mL or greater than about 375,000 ng·h/mL, respectively. In otherexamples, eslicarbazepine acetate may be administered to a patient in anamount resulting in an AUC_(0-τ) of eslicarbazepine greater than about595,000 ng·h/mL, greater than about 790,000 ng·h/mL, or more.

For example, a once-daily dose of about 400 mg may be administeredresulting in an area under the concentration curve (which corresponds tothe extent of systemic exposure) over the dosing interval (AUC_(0-τ)) ofeslicarbazepine greater than about 110,000 ng·h/mL. In other exemplaryembodiments, a once-daily dose of about 800 mg or about 1200 mg may beadministered resulting in an AUC_(0-τ) of eslicarbazepine greater thanabout 240,000 ng·h/mL or greater than about 375,000 ng·h/mL,respectively. In other examples, eslicarbazepine acetate may beadministered in a once-daily dose greater than about 1200 mg, such asabout 1800 mg, about 2400 mg, or more, to result in a respectiveAUC_(0-τ) of eslicarbazepine greater than about 595,000 ng·h/mL, greaterthan about 790,000 ng·h/mL, or more.

In one exemplary embodiment of the present disclosure, a once-daily dosemay be administered in a dosage comprising at least about 400 mg ofeslicarbazepine acetate. In another exemplary embodiment, a once-dailydose may be administered in a dosage comprising an amount ofeslicarbazepine acetate ranging from about 800 mg to about 1200 mg. Infurther exemplary embodiments, a once-daily dose may be administered ina dosage comprising an amount of eslicarbazepine greater than about 1200mg, such as about 1800 mg, about 2400 mg, or more.

The pharmaceutical composition comprising eslicarbazepine acetate mayoptionally be administered by any route known to those skilled in theart, and may be in a form chosen from, for example, tablets or oralsuspensions, or other forms.

The term “about” as used herein is meant to signify that the numbermodified by the term may be considered an approximation that may varydepending upon the desired properties or effect sought by the particularapplication, and thus should be considered to encompass the range thatone of skill in the art would understand to achieve the desired orrecited properties or effect.

A “method of treating” as described herein refers to administering to apatient the compound described in any amount effective to reduce theeffects of, counteract, or eliminate the disease or condition beingtreated, or the symptoms thereof.

A “method for increasing the exposure to eslicarbazepine in a patient”as described herein refers to administering to a patient the compounddescribed in any amount effective to increase the plasma concentrationof eslicarbazepine in the patient over the dosage interval. This may,for example, be an increase due to once-daily dosing relative totwice-daily dosing.

“Reducing epileptic seizures in a patient” as described herein refers toany decrease in the number, duration, or frequency of epileptic seizuresin a patient relative to the number, duration, or frequency of epilepticseizures experienced by the patient without treatment.

A “pharmacologically effective amount” of eslicarbazepine acetate in apharmaceutical composition as described herein refers to any amountsufficient to have the desired pharmacological activity.

All effective amounts as described herein will vary according to variouswell-known and understood factors, such as, for example, the conditionbeing treated and the physiological characteristics of the patient beingtreated. Accordingly, the effective amount will be well within theability of one skilled in the art to determine.

Study Materials and Methods

The following demonstrates, as one example of the present disclosure,the determination and administration of an effective amount of apharmaceutical composition comprising eslicarbazepine acetate to treatepilepsy in patients in need thereof. The effective amount of apharmaceutical composition to treat other diseases and/or conditionswould be determinable by one skilled in the art based on the techniquesand concepts disclosed herein and known in the art.

The effects of eslicarbazepine acetate in humans was studied in at leastthe following clinical studies. In the first study, a placebo-controlledtherapeutic exploratory study, once-daily and twice-daily dosing wascompared in epileptic patients refractory to standard anti-epilepticdrug therapy. In the second study, healthy subjects received either aonce-daily (o.d.) oral dose of 900 mg of eslicarbazepine acetate or atwice-daily (b.i.d.) dose of 450 mg of eslicarbazepine acetate. In thethird study, healthy subjects received single oral doses ofeslicarbazepine acetate ranging from 20 mg to 2400 mg, and repeatedonce-daily (o.d.) oral doses ranging from 400 mg to 2400 mg ofeslicarbazepine acetate.

The bioequivalence of tablets and oral suspensions was proven in arelative bioavailability study.

Study in Epileptic Patients

This clinical trial was a double-blind, randomized, placebo-controlledstudy performed by 20 centers in Croatia, Czech Republic, Germany,Lithuania and Poland. The stated objectives of the study were to assessthe efficacy and safety of BIA 2-093 as adjunctive therapy in patientswith refractory partial epilepsy. In total, 143 patients aged 18-65years with at least 4 partial-onset seizures per month in spite oftreatment with 1 or 2 antiepileptic drugs (AEDs) (e.g., phenyloin,valproate, primidone, phenobarbital, lamotrigine, gabapentin, topiramateor clonazepam) were randomly assigned to one of three groups: treatmentwith placebo (n=47), BIA 2-093 once-daily (n=50), or BIA 2-093twice-daily (n=46), during 12 weeks (plus 1 week of tapering off). Forthe first 4 weeks, daily dose was 400 mg. Then, daily doses wereincreased to 800 mg (weeks 5-8), and finally to 1200 mg (weeks 9-12).Tablets with strengths of 200 mg, 400 mg, and 600 mg eslicarbazepineacetate and placebo tablets were manufactured by BIAL (S. Mamede doCoronado, Portugal) in accordance with Good Manufacturing Practice. Theassay plasma to determine the concentration of BIA 2-005 was performedwith a non-chiral method using isocratic liquid chromatography (LC) withsingle quadrupole mass spectrometric detection (MS), as describedherein. See, e.g., Almeida I and Almeida II.

Study in Healthy Human Volunteers Trial A

This human pharmacology trial was a study to investigate thesteady-state pharmacokinetics of once-daily and twice-daily regimens ofeslicarbazepine acetate in healthy subjects. The study was a singlecenter, open-label, randomized, two-way crossover study in 12 healthyvolunteers (6 males and 6 females) that consisted of two 8-day treatmentperiods separated by a washout period of 10-15 days. On each of thetreatment periods the volunteers received either a daily oral dose ofeslicarbazepine acetate 900 mg once-daily (o.d.) or eslicarbazepineacetate 450 mg twice-daily (b.i.d.). Tablets with a strength of 450 mgof eslicarbazepine acetate, manufactured by BIAL (S. Mamede do Coronado,Portugal) in accordance with Good Manufacturing Practice, were used.

Blood samples for drug plasma assays were taken at the following times:

Phase A:

-   -   pre-dose, and ½, 1, 1½, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, and        96 hours post-dose;

Phase B:

-   -   day 5 to day 11 (inclusive): before the daily dose (for “trough”        concentrations assay);    -   day 12: pre-dose, and ½, 1, 1½, 2, 3, 4, 6, 8, 12, 24, 36, 48,        72, 96, and 120 hours post-dose.        Blood samples were drawn either by direct venipuncture or via an        intravenous catheter into lithium heparin tubes and centrifuged        at approximately 1500 g for 10 minutes at 4° C. The resulting        plasma was separated into 2 equal aliquots of 1 mL and stored at        −20° C. until required for analysis.

Plasma concentrations of eslicarbazepine acetate, eslicarbazepine, andR-licarbazepine were determined using isocratic liquid chromatography(LC) with single quadrupole mass spectrometric detection (MS).

The method involved the addition of 500 μL of approximately 0.5 μg/mL of10,11-dihydrocarbamazepine (internal standard prepared inacetonitrile:water, 3:97, v:v) to 250 μL of plasma (centrifuged at 1800rpm, prior to analysis) in a polypropylene tube. After vortex mixing for10 seconds, the mixture was transferred to a Schleicher and SchuellC18/100 mg 96 well solid phase extraction plate. Each well waspreconditioned with 800 μL methanol, followed by 800 μL acetonitrile and800 μL acetonitrile:water (3:97, v:v) prior to application of the totalsample volume. Each polypropylene tube was then washed with 500 μLacetonitrile:water (3:97, v:v) and the washings transferred to therespective well. The compounds were eluted into a collection plate with750 μL acetonitrile and the extract evaporated to dryness underoxygen-free nitrogen, at 40° C. All solid phase extraction manipulationswere undertaken using the Tomtec QUADRA 96® Model 320 system and avacuum was applied at each elution step. The final extract wasreconstituted in 100 μL of water:methanol (90:10, v:v) and mixed. Thecollection plate was then centrifuged at approximately 3000 rpm (atapproximately 4° C., for approximately 10 minutes) prior to analysis. Analiquot of the final extract (10 μL) was injected onto the LC-MS system.

The LC-MS system used in the analysis consisted of a Perkin Elmer series200 micro pump, a Perkin Elmer series 200 autosampler, and a PerkinElmer/Sciex API 150EX single quadrupole mass spectrometer fitted with aTurbo IonSpray® source. Separation was achieved using a LichroCART 250-4ChiraDex column (β-cyclodextrin, 5 μm), a LichroCART 4-4 ChiraDex columnguard column (β-cyclodextrin, 5 μm), a Jones Chromatography 7971 columnheater at 50° C., a mobile phase A (0.2 mM sodium acetate, aq) and amobile phase B (0.2 mM sodium acetate, MeOH). The MS detector wasoperated in positive ion mode with mass transitions for BIA 2-093,eslicarbazepine, R-licarbazepine, and the internal standard of 319.16amu (200 ms), 277.08 amu (200 ms), 277.08 amu (200 ms) and 261.05 amu(200 ms), respectively. The limit of quantification of the assay was 10ng/mL for eslicarbazepine acetate and 100 ng/mL for eslicarbazepine andR-licarbazepine.

Eslicarbazepine acetate,(S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;eslicarbazepine, (S)-(+)-10,11-dihydro-10-hydroxy-5Hdibenz/b,f/azepine-5-carboxamide; and R-licarbazepine,(R)-(−)-10,11-dihydro-10-hydroxy-5H dibenz/b,f/azepine-5-carboxamide,were synthesized in the Laboratory of Chemistry, BIAL, withpurities>99.5%. The internal standard, 10,11-dihydrocarbamazepine wassupplied by Sigma-Aldrich (St. Louis, Mo.).

The pharmacokinetic parameters were derived from non-compartmentalanalysis using WinNonlin (Version 4.0, Pharsight Corporation, MountainView, Calif.). The following parameters were derived, where appropriate,from the individual plasma concentration-time profiles: maximum observedplasma concentration (C_(max)); time of occurrence of C_(max) (t_(max));area under the plasma concentration versus time curve (AUC) from timezero to the last sampling time (t) at which concentrations were at orabove the limit of quantification (AUC_(0-t)), calculated by the lineartrapezoidal rule; AUC over the dosing interval (AUC_(τ)), i.e., 24 hoursand 12 hours in the once-daily and the twice-daily group, respectively;AUC from time zero to infinity (AUC_(0-∞)), calculated fromAUC_(0-t)+(C_(last)/λ_(z)), where C_(last) is the last quantifiableconcentration; apparent terminal rate constant (λ_(z)) calculated bylog-linear regression of the terminal segment of the plasmaconcentration versus time curve; apparent terminal half-life (t_(1/2)),calculated from ln 2/λ_(z).

Actual sampling times were used for the pharmacokinetic analysis. Wherean AUC was extrapolated to infinity, the percentage of the extrapolatedarea to the total area was assessed; if greater than 20%, the AUC valuewas flagged as unreliable. Plasma concentrations below the limit ofquantification of the assay (BLQ) were taken as zero for allcalculations. All calculations were made using raw data. Values fort_(max) were displayed as nominal times.

Summary statistics for each group and schedule sampling time werereported, as appropriate, using the geometric mean, arithmetic mean,standard deviation (SD), coefficient of variation (CV), median, minimum,and maximum. Comparisons between elderly versus young groups for thesingle-dose and multiple-dose data were based on analysis of variance(one-way ANOVA) of the logarithmic transformed C_(max), AUC_(τ) andAUC_(0-∞) parameters. A t_(max) comparison between age groups wasperformed assuming a non-parametric approach using the Wilcoxon signedrank test. In addition, differences in logarithmic transformedparameters (C_(max), AUG_(τ) and AUC_(0-∞)) and their associated 95%confidence intervals (95Cl) were estimated between age groups to takethe form of ratios on a linear scale. The median values and differencesof t_(max) between age groups and 95% Cl were reported. All tests ofsignificance were performed at the p=0.05 level. The statistical packageSAS (Version 8.2, SAS Institute Inc, Cary, N.C.) was used.

Trial B

This human pharmacology trial was a study to determine thepharmacokinetics of eslicarbazepine acetate following single andrepeated doses. The study integrated the results of three double-blind,randomized, placebo-controlled trials. To measure the pharmacokineticsof eslicarbazepine acetate following single doses, oral single doses ofeslicarbazepine acetate ranging from 20 mg to 2400 mg were administeredto healthy young male subjects (6 subjects per dose). Thepharmacokinetics of eslicarbazepine acetate following repeated doseswere measured by administering repeated oral doses ranging from 400 mgto 2400 mg of eslicarbazepine acetate to healthy young male subjects (6subjects per dose) over a period of 8 days. Analytical test methods andexperimental procedures were similar to those described for Trial Aabove.

Study Results Study in Epileptic Patients Baseline Characteristics

At baseline, the treatment groups were homogenous with regard to age,height, weight, and body mass index. All 143 patients were Caucasian.With respect to gender, there were relatively more female patients inthe twice-daily group than in the once-daily and placebo groups (65.2%,56.0% and 57.4%, respectively); this difference did not significantlyaffect the results. No significant differences were found in the numberof AEDs used: respectively 30.0%, 34.8% and 29.8% of patients in theonce-daily, twice-daily, and placebo groups were treated with 1 AED; theremaining patients were treated with 2 AEDs. The most frequently usedconcomitant AEDs were valproic acid (68.0%, 60.9% and 66.0% of patientsin the once-daily, twice-daily, and placebo groups, respectively),topiramate (36.0%, 34.8%, and 21.3%, respectively) and lamotrigine(30.0%, 28.3%, and 31.9%, respectively).

At baseline, mean duration of epilepsy was 16.7, 19.5, and 20.0 years inthe once-daily, twice-daily, and placebo groups, respectively. Withrespect to seizure type frequency, IA simple partial, IB complexpartial, and IC partial evolving to secondarily generalized were presentin, respectively, 34.0%, 72.0%, and 80.0%, in the once-daily group;37.0%, 71.7%, and 80.4%, in the twice-daily group; and 27.7%, 80.9%, and72.3%, in the placebo group. The mean of total number of seizures permonth prior to the study was 14.1, 13.6, and 11.8, in the once-daily,twice-daily, and placebo groups, respectively.

Efficacy Results

The proportion of patients with a 50% or greater reduction in seizurefrequency in the treatment period compared to the baseline period in theintention-to-treat (ITT) population (n=143) was the primary efficacyendpoint. At the dose of 1200 mg/day (weeks 9-12), the proportion ofresponders in the once-daily group (54%) was significantly higher(p=0.008) than in the placebo group (28%). The proportion of respondersin the once-daily group (54%) was also higher than in the twice-daily(41%) group. At the dose of 800 mg/day (weeks 5-8), the proportion ofresponders in the once-daily group (58%) was significantly higher(p<0.05) than in the twice-daily (33%) and placebo (38%) groups. At thisdose level, no significant difference was found between the twice-dailyand the placebo groups.

Secondary endpoints include the reduction in total seizure frequency,proportion of seizure-free patients, distribution of responders,comparison of once and twice daily regimens, and investigator's andpatient's global evaluation.

The greatest decrease in the number of seizures was achieved with 1200mg and 800 mg once-daily doses, and the results with the once-dailygroup were better than those obtained in the twice-daily group (FIG. 1).For all dosages (400 mg, 800 mg, and 1200 mg), patients receivingonce-daily doses of eslicarbazepine acetate had a substantially greaterreduction in the number of seizures compared to patients in thetwice-daily and placebo groups.

The number of seizures in patients receiving 1200 mg and 800 mgonce-daily doses of eslicarbazepine acetate was reduced by 59.5% and55.8%, respectively. In comparison, seizures in patients receiving 1200mg and 800 mg twice-daily doses reduced by 47.5% and 38.1%,respectively. Patients receiving a 400 mg once-daily dose ofeslicarbazepine acetate experienced a 38.9% reduction in the number ofseizures, almost twice the reduction in seizures observed in patientsreceiving 400 mg twice-daily doses of eslicarbazepine acetate (20.2%).

At the end of the 12-week treatment phase, 27.9% of the patients in theonce-daily dosing group became seizure-free.

In addition, the assessment of efficacy by the investigator(CGI—Clinical Global Impression) and of acceptability by patient wasrated best in the once-daily group.

Pharmacokinetic Results

Plasma/serum samples for the “trough” (pre-dose) levels of BIA 2-005 andconcomitant AEDs were collected at all visits but V5 (post-study visit).The objective was to characterize the influence of eslicarbazepineacetate on the pharmacokinetic behavior of the concomitant AEDs (e.g.,phenyloin, valproate, primidone, phenobarbital, lamotrigine, gabapentin,topiramate, and clonazepam). The mean trough plasma concentrations ofBIA 2-005 are displayed in Table 1. As shown in FIG. 2, no significantdifferences in the BIA 2-005 trough (pre-dose) values between theonce-daily and twice-daily groups were found.

TABLE 1 Trough plasma concentrations of BIA 2-005 following oraladministration of eslicarbazepine acetate once-daily (o.d.) andtwice-daily (b.i.d) 400 mg/day 800 mg/day 1200 mg/day o.d. b.i.d. o.d.b.i.d. o.d. b.i.d. group group group group group group Mean (μg/mL) 4.0(3.2) 4.9 (2.3) 10.7 (7.0) 13.5 (9.6) 14.6 (8.8) 15.5 (8.8)Results expressed as arithmetic means with the correspondent standarddeviations (sd) in parenthesis.

The relatively small number of patients being administered phenyloin,primidone, phenobarbital, gabapentin, and clonazepam precluded theappropriate characterization of the eventual effect of eslicarbazepineacetate on the pharmacokinetic behavior of these concomitant AEDs. Forvalproate, lamotrigine and topiramate, the number of patients was alsosmall, but an exploratory analysis of the effect of eslicarbazepineacetate on the trough blood values of these concomitant AEDs wasperformed. The mean trough serum concentrations of valproate were notsignificantly changed by concomitant administration of eslicarbazepineacetate once-daily (7.0%; 95% IC: −7.6, 36.2) or twice-daily (6.3%; 95%IC: −7.5, 20.1). In the placebo group, a significant increase in theserum levels of valproate was noticed (25.4%; 95% IC: 5.1, 45.8). Withrespect to lamotrigine, its serum levels were not significantly changedwhen eslicarbazepine acetate once-daily (−10.0%; 95% IC: −46.2, 26.2) orplacebo (12.6%; 95% IC: −12.6, 37.8) were added to therapy. Witheslicarbazepine acetate twice-daily, the serum levels of lamotriginedecreased significantly (−46.7%; 95% IC: −69.7; −23.8). With respect totopiramate, its serum levels were not significantly changed wheneslicarbazepine acetate once-daily (−15.2%; 95% IC: −34.8, 4.4) wasadded to the therapy. With eslicarbazepine acetate twice-daily, theserum levels of topiramate decreased significantly (−32.4%; 95% IC:−49.5; −15.3). One skilled in the art will know whether a change inserum levels is significant.

Study in Healthy Human Volunteers Trial A Pharmacokinetic Results

Eslicarbazepine acetate was shown to be extensively metabolized toeslicarbazepine and, in a minor extent, to R-licarbazepine. Thesteady-state of eslicarbazepine plasma concentrations was attained at 4to 5 days of administration in both groups.

Following the last dose, in the once-daily group, mean C_(max) ofeslicarbazepine and R-licarbazepine was, respectively, 22,210 ng/mL and674 ng/mL and occurred at (median t_(max)) 2.45 hours and 9.42 hourspost-dose, respectively. Mean AUC_(0-t) of eslicarbazepine andR-licarbazepine was 381,601 ng·h/mL and 19,600 ng·h/mL, respectively. Inthe twice-daily group, mean C_(max) of eslicarbazepine andR-licarbazepine was 16,667 ng/mL and 718 ng/mL, respectively, andoccurred (median t_(max)) at 2.09 hours and 6.40 hours post-dose,respectively. Mean AUC_(0-t) of eslicarbazepine and R-licarbazepine was283,014 ng·h/mL and 19,661 ng·h/mL, respectively. Following multipleadministration of eslicarbazepine acetate for 8 days, eslicarbazepinewas shown to be the major metabolite, representing approximately 95% and96% of total systemic drug exposure (as assessed by AUC₀₋₂₄) inonce-daily and twice-daily subjects, respectively. Tables 2 and 3 depictthe eslicarbazepine and R-licarbazepine pharmacokinetic parameters inthe once-daily and twice-daily groups following the last dose ofeslicarbazepine acetate. The total exposure of healthy volunteers toeslicarbazepine in the once-daily group was unexpectedly at least 26%higher than in the twice-daily group.

TABLE 2 Mean pharmacokinetic parameters of eslicarbazepine andR-licarbazepine following a multiple oral dose of 900 mg eslicarbazepineacetate once-daily. C_(max) AUC_(0-t) AUC_(0-τ) AUC_(0-∞) (ng/ t_(max)(ng · h/ (ng · h/ (ng · h/ t_(1/2) mL) (h) mL) mL) mL) (h)Eslicarbazepine n 11 11 11 11 11 11 A_(mean) 22210 2.45 381601 294019389344 9.12 SD 7257 0.879 95368 58364 97383 1.19 R-licarbazepine n 12 1212 12 12 12 A_(mean) 674 9.42 19600 13397 23989 15.0 SD 184 6.48 67633187 7144 3.41 n = Number of subjects; A_(mean) = Arithmetic mean; SD =Standard deviation.

TABLE 3 Mean pharmacokinetic parameters of eslicarbazepine andR-licarbazepine following a multiple oral dose of 900 mg eslicarbazepineacetate twice-daily. C_(max) AUC_(0-t) AUC_(0-τ) AUC_(0-∞) (ng/ t_(max)(ng · h/ (ng · h/ (ng · h/ t_(1/2) mL) (h) mL) mL) mL) (h)Eslicarbazepine n 11 11 11 11 11 11 A_(mean) 16667 2.09 283014 142080289792 9.17 SD 3981 0.664 74203 25933 74346 1.49 R-licarbazepine n 10 1010 10 10 10 A_(mean) 718 6.40 19661 7783 23807 14.8 SD 184 3.06 60492083 7150 4.09 n = Number of subjects; A_(mean) = Arithmetic mean; SD =Standard deviation

Trial B Pharmacokinetic Results

As in Trial A, eslicarbazepine acetate was extensively metabolized toeslicarbazepine and, in a minor extent, to R-licarbazepine. Thesteady-state of eslicarbazepine plasma concentrations was attained at 4to 5 days of once-daily dosing.

Following the last dose, in the repeated once daily group, mean C_(max)of eslicarbazepine ranged from 8,800 ng/ML·(16.0% coefficient ofvariation, CV) for 400 mg doses of eslicarbazepine acetate to 56,500ng/ML·(20.0% CV) for 2400 mg doses of eslicarbazepine acetate. Themaximum plasma concentration for all dosages occurred (median t_(max))at 2 hours to 3.5 hours. The mean area under the concentration for thedosing interval of 24 hours, AUC_(0-24 h), ranged from 126,300 ng·h/mLfor 400 mg once-daily doses of eslicarbazepine acetate to 905,900ng·h/mL for 2400 mg once-daily doses of eslicarbazepine acetate. Tables4 and 5 depict the eslicarbazepine and R-licarbazepine pharmacokineticparameters following the single dose of eslicarbazepine acetate and thepharmacokinetic parameters following the last of the repeated doses ofeslicarbazepine acetate.

TABLE 4 Mean pharmacokinetic parameters of eslicarbazepine andR-licarbazepine following single doses of eslicarbazepine acetate (n = 6subjects per dose group). Mean Mean AUC_(0-24 h) apparent Mean C_(max)Median t_(max) ng · h/mL t_(1/2) Dose ng/mL (% CV) h (range) (% CV) h (%CV)  20 mg   300 (18.7) 0.8 (0.5-0.8)  2,400 (16.2)  9.1 (15.9)  50 mg  900 (24.7) 0.8 (0.5-2)    6,700 (12.7) 8.1 (9.1) 100 mg  1,500 (13.8)1.5 (0.5-2)    16,400 (11.7) 9.3 (8.7) 200 mg  2,900 (16.2) 1.5(0.8-2.5)  30,500 (23.7)  8.4 (18.8) 400 mg  5,200 (11.6) 4 (4-5)   81,500 (10.8) 11.7 (18.6) 600 mg  8,500 (20.0) 4 (0.5-5) 119,700 (17.4)12.3 (14.8) 900 mg 15,000 (18.2) 2.3 (0.8-4)   210,300 (10.6) 16.3(31.9) 1200 mg  18,600 (16.3) 4 (2-6)   285,700 (16.7) 16.5 (6.8)  1800mg  34,600 (16.3) 3.5 (3-6)    507,600 (17.0) 11.8 (11.7) 2400 mg 35,900 (42.6) 3 (1.5-6) 445,600 (26.1) 11.1 (21.1) CV = Coefficient ofvariation (%); C_(max) = Maximum plasma concentration; AUC_(0-24 h) =Area under the curve of plasma concentration-time over 24 h; t_(max) =Time to C_(max); t_(1/2) = Elimination half-life

TABLE 5 Mean pharmacokinetic parameters of eslicarbazepine andR-licarbazepine following the last dose of an 8-day repeated doseregimen of eslicarbazepine acetate (n = 6 subjects per dose group). MeanC_(max) Median t_(max) Mean AUC_(0-24 h) Mean apparent t_(1/2) Doseng/mL (% CV) h (range) ng · h/mL (% CV) h (% CV)  400 mg o.d. 8,800(16.0) 3 (0.5-7) 126,300 (11.7) 9.50 (18.8)  800 mg o.d. 18,700 (14.0)3.5 (1-7)   268,400 (10.3) 12.3 (22.9) 1200 mg o.d. 25,500 (10.8) 3(0.5-6) 423,000 (10.9) 13.1 (20.1) 1800 mg o.d. 47,700 (23.3) 2 (0.5-4)740,300 (19.6) 11.3 (28.8) 2400 mg o.d. 56,500 (20.0) 2 (1.5-8) 905,900(12.8) 10.4 (24.1) CV = Coefficient of variation (%); C_(max) = Maximumplasma concentration; AUC_(0-24 h) = Area under the curve of plasmaconcentration-time over 24 h; t_(max) = Time to C_(max); t_(1/2) =Elimination half-life

Study Discussion

Once-daily administration of eslicarbazepine acetate was found to bemore efficacious than the same total dosage divided into twice-dailydoses, and is clearly more efficacious in reducing epileptic seizuresthan placebo. 800 mg and 1200 mg once-daily doses of eslicarbazepineacetate were shown to be noticeably more efficacious in reducingepileptic seizures than twice-daily doses achieving the same total dailydosage.

Eslicarbazepine acetate was shown to be extensively metabolized toeslicarbazepine and, in a minor extent, to R-licarbazepine.Eslicarbazepine represented between 95% and 98% of total systemic drugexposure (as assessed by AUC_(0-τ), i.e., AUC over the dosing interval)and, therefore, is believed to be mainly responsible for pharmacologicalactivity following administration of eslicarbazepine acetate. Plasmaconcentrations of parent drug (eslicarbazepine acetate) weresystematically found to be below the limit of quantification. Withmultiple-dosing, steady-state plasma concentrations were attained at 4to 5 days of administration in both groups, consistent with an effectivehalf-life on the order of about 20-24 hours.

The kinetic profile of eslicarbazepine in the once-daily group wasmarkedly different from the twice-daily group with statisticaldifferences found for some of the pharmacokinetic parameters assessed(C_(max), AUC_(0-t) and AUC_(0-∞)) following multiple oral dosing ofeslicarbazepine acetate. In fact, the total exposure of healthyvolunteers to eslicarbazepine in the once-daily group was unexpectedlyat least 26% higher than in the twice-daily group. This unexpectedresult is in line with finding in epileptic patients that once-dailyadministration of eslicarbazepine acetate was more efficacious than thesame total daily dosage divided into twice-daily doses. Though thisresult might imply that the enhanced clinical efficacy would result froman increase in the rate (C_(max)) and extent (AUC) of exposure toeslicarbazepine, the reasons for such an enhanced extent of exposureafter once-daily versus twice-daily administration remain unexplained.

In addition to the exemplary aspects and embodiments described above,further aspects and embodiments will become apparent to those skilled inthe art by study of the foregoing description. Those skilled in the artwill recognize that certain modifications of the above description arepossible, and such modifications are considered to be within the scopeof the invention. It is therefore intended that the following appendedclaims (including any amendments thereto) and any claims hereafterintroduced should be interpreted to include all such aspects,embodiments, and modifications.

1-29. (canceled)
 30. A method for treating epilepsy in a patient in needthereof, comprising: administering to the patient a once-daily dose of apharmaceutical composition comprising eslicarbazepine acetate in apharmacologically effective amount.
 31. The method according to claim30, wherein the once-daily dose is administered in an amount resultingin a maximum observed plasma concentration, C_(max), of eslicarbazepinegreater than about 7,400 ng/mL.
 32. The method according to claim 31,wherein the once-daily dose is administered in an amount resulting in aC_(max) of eslicarbazepine greater than about 12,000 ng/mL.
 33. Themethod according to claim 30, wherein the once-daily dose isadministered in an amount resulting in an area under the concentrationcurve, AUC_(0-τ), of eslicarbazepine greater than about 110,000 ng·h/mL,wherein τ is the dosing interval.
 34. The method according to claim 33,wherein the once-daily dose is administered in an amount resulting in aAUC_(0-τ) of eslicarbazepine greater than about 240,000 ng·h/mL.
 35. Themethod according to claim 30, wherein the once-daily dose isadministered in a dosage comprising at least about 400 mg ofeslicarbazepine acetate.
 36. The method according to claim 35, whereinthe once-daily dose is administered in a dosage comprising an amount ofeslicarbazepine acetate ranging from about 800 mg to about 2400 mg. 37.The method according to claim 30, wherein the active ingredient in thepharmaceutical composition consists essentially of eslicarbazepineacetate.
 38. The method according to claim 30, wherein the once-dailydose of the pharmaceutical composition comprising eslicarbazepineacetate is administered as adjunctive therapy to a patient being treatedwith at least one other anti-epileptic drug.
 39. The method according toclaim 38, wherein the serum concentration of the at least one otheranti-epileptic drug is not significantly decreased by the once-dailydose of the pharmaceutical composition comprising eslicarbazepineacetate.
 40. The method according to claim 38, wherein the at least oneother anti-epileptic drug is chosen from valproate, lamotrigine,topiramate, and combinations thereof.
 41. The method according to claim30, wherein the epilepsy is refractory partial epilepsy.
 42. The methodaccording to claim 30, wherein the pharmaceutical composition isadministered in the form of a tablet or an oral suspension.
 43. A methodfor reducing epileptic seizures in a patient, comprising: administeringto the patient a once-daily dose of a pharmaceutical compositioncomprising eslicarbazepine acetate in a pharmacologically effectiveamount.
 44. The method according to claim 43, wherein the activeingredient in the pharmaceutical composition consists essentially ofeslicarbazepine acetate.
 45. The method according to claim 43, whereinthe once-daily dose is administered in a dosage comprising at leastabout 400 mg of eslicarbazepine acetate.
 46. The method according toclaim 45, wherein the once-daily dose is administered in a dosagecomprising an amount of eslicarbazepine acetate ranging from about 800mg to about 2400 mg.
 47. The method according to claim 30, wherein theonce-daily dose is administered in an amount resulting in a maximumobserved plasma concentration, C_(max), of eslicarbazepine up to about58,800 ng/mL.
 48. The method according to claim 32, wherein theonce-daily dose is administered in an amount resulting in a C_(max) ofeslicarbazepine greater than about 22,700 ng/mL.
 49. The methodaccording to claim 48, wherein the once-daily dose is administered in anamount resulting in a C_(max) of eslicarbazepine greater than about36,500 ng/mL.
 50. The method according to claim 49, wherein theonce-daily dose is administered in an amount resulting in a C_(max) ofeslicarbazepine greater than about 45,200 ng/mL.
 51. The methodaccording to claim 30, wherein the once-daily dose is administered in anamount resulting in a maximum observed plasma concentration, C_(max), ofeslicarbazepine up to about 67,800 ng/mL.
 52. The method according toclaim 30, wherein the once-daily dose is administered in an amountresulting in an area under the concentration curve, AUC_(0-τ), ofeslicarbazepine up to about 885,000 ng·h/mL, wherein τ is the dosinginterval.
 53. The method according to claim 30, wherein the once-dailydose is administered in an amount resulting in an area under theconcentration curve, AUC_(0-τ), of eslicarbazepine up to about 1,000,000ng·h/mL, wherein τ is the dosing interval.
 54. The method according toclaim 34, wherein the once-daily dose is administered in an amountresulting in a AUC_(0-τ) of eslicarbazepine greater than about 375,000ng·h/mL.
 55. The method according to claim 54, wherein the once-dailydose is administered in an amount resulting in a AUC_(0-τ) ofeslicarbazepine greater than about 595,000 ng·h/mL.
 56. The methodaccording to claim 55, wherein the once-daily dose is administered in anamount resulting in a AUC_(0-τ) of eslicarbazepine greater than about790,000 ng·h/mL.
 57. The method according to claim 35, wherein theonce-daily dose is administered in a dosage comprising at least about800 mg of eslicarbazepine acetate.
 58. The method according to claim 57,wherein the once-daily dose is administered in a dosage comprising atleast about 1200 mg of eslicarbazepine acetate.
 59. The method accordingto claim 35, wherein the once-daily dose is administered in a dosagecomprising an amount of eslicarbazepine acetate ranging from about 800mg to about 1200 mg.
 60. The method according to claim 35, wherein theonce-daily dose is administered in a dosage comprising an amount ofeslicarbazepine acetate ranging from about 400 mg to about 1200 mg. 61.The method according to claim 42, wherein the oral suspension comprisesat least one excipient, auxiliary substance or carrier material.
 62. Themethod according to claim 61, wherein the at least one excipient,auxiliary substance or carrier material is selected from the groupconsisting of xanthan gum, macrogol stearate, methylparaben,propylparaben, saccharin sodium, sorbitol, buffers, flavourings andcombinations thereof.
 63. The method according to claim 30, wherein uponadministration of the pharmaceutical composition, the number, duration,or frequency of epileptic seizures in a patient decreases relative tothe number, duration or frequency of epileptic seizures in a patientwithout treatment.
 64. The method according to claim 30, wherein thefrequency of epileptic seizures is reduced by 50% or more.
 65. Themethod according to claim 30, wherein upon administration of thepharmaceutical composition patients become seizure-free relative to apatient without treatment.
 66. The method according to claim 30, whereinthe patient is an adult.
 67. The method according to claim 30, whereinthe patient is aged 18 to 65 years.
 68. The method according to claim30, wherein the pharmaceutical composition is administered orally. 69.The method according to claim 43, wherein the once-daily dose isadministered in an amount resulting in a maximum observed plasmaconcentration, C_(max), of eslicarbazepine greater than about 7,400ng/mL.
 70. The method according to claim 69, wherein the once-daily doseis administered in an amount resulting in a C_(max) of eslicarbazepinegreater than about 12,000 ng/mL.
 71. The method according to claim 43,wherein the once-daily dose is administered in an amount resulting in amaximum observed plasma concentration, C_(max), of eslicarbazepine up toabout 58,800 ng/mL.
 72. The method according to claim 70, wherein theonce-daily dose is administered in an amount resulting in a C_(max) ofeslicarbazepine greater than about 22,700 ng/mL.
 73. The methodaccording to claim 72, wherein the once-daily dose is administered in anamount resulting in a C_(max) of eslicarbazepine greater than about36,500 ng/mL.
 74. The method according to claim 73, wherein theonce-daily dose is administered in an amount resulting in a C_(max) ofeslicarbazepine greater than about 45,200 ng/mL.
 75. The methodaccording to claim 43, wherein the once-daily dose is administered in anamount resulting in a maximum observed plasma concentration, C_(max), ofeslicarbazepine up to about 67,800 ng/mL.
 76. The method according toclaim 43, wherein the once-daily dose is administered in an amountresulting in an area under the concentration curve, AUC_(0-τ), ofeslicarbazepine up to about 885,000 ng/mL, wherein τ is the dosinginterval.
 77. The method according to claim 43, wherein the once-dailydose is administered in an amount resulting in an area under theconcentration curve, AUC_(0-τ), of eslicarbazepine up to about 1,000,000ng/mL, wherein τ is the dosing interval.
 78. The method according toclaim 43, wherein the once-daily dose is administered in an amountresulting in an area under the concentration curve, AUC_(0-τ), ofeslicarbazepine greater than about 110,000 ng·h/mL, wherein τ is thedosing interval.
 79. The method according to claim 78, wherein theonce-daily dose is administered in an amount resulting in a AUC_(0-τ) ofeslicarbazepine greater than about 240,000 ng·h/mL.
 80. The methodaccording to claim 79, wherein the once-daily dose is administered in anamount resulting in a AUC_(0-τ) of eslicarbazepine greater than about375,000 ng·h/mL.
 81. The method according to claim 80, wherein theonce-daily dose is administered in an amount resulting in a AUC_(0-τ) ofeslicarbazepine greater than about 595,000 ng·h/mL.
 82. The methodaccording to claim 81, wherein the once-daily dose is administered in anamount resulting in a AUC_(0-τ) of eslicarbazepine greater than about790,000 ng·h/mL.
 83. The method according to claim 45, wherein theonce-daily dose is administered in a dosage comprising at least about800 mg of eslicarbazepine acetate.
 84. The method according to claim 83,wherein the once-daily dose is administered in a dosage comprising atleast about 1200 mg of eslicarbazepine acetate.
 85. The method accordingto claim 45, wherein the once-daily dose is administered in a dosagecomprising an amount of eslicarbazepine acetate ranging from about 800mg to about 1200 mg.
 86. The method according to claim 45, wherein theonce-daily dose is administered in a dosage comprising an amount ofeslicarbazepine acetate ranging from about 400 mg to about 1200 mg. 87.The method according to claim 43, wherein the once-daily dose of thepharmaceutical composition comprising eslicarbazepine acetate isadministered as adjunctive therapy to a patient being treated with atleast one other anti-epileptic drug.
 88. The method according to claim87, where the serum concentration of the at least one otheranti-epileptic drug is not significantly decreased by the once-dailydose of the pharmaceutical composition comprising eslicarbazepineacetate.
 89. The method according to claim 87, wherein the at least oneother anti-epileptic drug is chosen from valproate, lamotrigine,topiramate, and combinations thereof.
 90. The method according to claim43, wherein the pharmaceutical composition is administered in the formof a tablet or an oral suspension.
 91. The method according to claim 90,wherein the oral suspension comprises at least one excipient, auxiliarysubstance or carrier material.
 92. The method according to claim 91,wherein the at least one excipient, auxiliary substance or carriermaterial is selected from the group consisting of xanthan gum, macrogolstearate, methylparaben, propylparaben, saccharin sodium, sorbitol,buffers, flavourings and combinations thereof.
 93. The method accordingto claim 43, wherein the epilepsy is refractory partial epilepsy. 94.The method according to claim 43, wherein upon administration of thepharmaceutical composition, the number, duration, or frequency ofepileptic seizures in a patient decreases relative to the number,duration or frequency of epileptic seizures in a patient withouttreatment.
 95. The method according to claim 43, wherein the reductionin frequency of epileptic seizures is 50% or more.
 96. The methodaccording to claim 43, wherein upon administration of the pharmaceuticalcomposition patients become seizure-free relative to a patient withouttreatment.
 97. The method according to claim 43, wherein the patient isan adult.
 98. The method according to claim 43, wherein the patient isaged 18 to 65 years.
 99. The method according to claim 43, wherein thepharmaceutical composition is administered orally.
 100. A pharmaceuticalcomposition comprising eslicarbazepine acetate in a pharmacologicallyeffective amount for use in treating epilepsy in a patient in needthereof in a once-daily dose.
 101. The pharmaceutical compositionaccording to claim 100, wherein the composition is in a form foradministration in an amount resulting in a maximum observed plasmaconcentration, C_(max), of eslicarbazepine greater than about 7,400ng/ml.
 102. The pharmaceutical composition according to claim 101,wherein the composition is in a form for administration in an amountresulting in a C_(max) of eslicarbazepine greater than about 12,000ng/ml.
 103. The pharmaceutical composition according to claim 100,wherein the composition is in a form for administration in an amountresulting in a maximum observed plasma concentration, C_(max) ofeslicarbazepine up to about 58,800 ng/mL.
 104. The pharmaceuticalcomposition according to claim 102, wherein the composition is in a formfor administration in an amount resulting in a C_(max) ofeslicarbazepine greater than about 22,700 ng/mL.
 105. The pharmaceuticalcomposition according to claim 104, wherein the composition is in a formfor administration in an amount resulting in a C_(max) ofeslicarbazepine greater than about 36,500 ng/mL.
 106. The pharmaceuticalcomposition according to claim 105, wherein the composition is in a formfor administration in an amount resulting in a C_(max) ofeslicarbazepine greater than about 45,200 ng/mL.
 107. The pharmaceuticalcomposition according to claim 100, wherein the composition is in a formfor administration in an amount resulting in a maximum observed plasmaconcentration, C_(max) of eslicarbazepine up to about 67,800 ng/mL. 108.The pharmaceutical composition according to claim 100, wherein thecomposition is in a form for administration in an amount resulting in anarea under the concentration curve, AUC_(0-τ), of eslicarbazepine up toabout 885,000 ng·h/mL, wherein τ is the dosing interval.
 109. Thepharmaceutical composition according to claim 100, wherein thecomposition is in a form for administration in an amount resulting in anarea under the concentration curve, AUC_(0-τ), of eslicarbazepine up toabout 1,000,000 ng·h/mL, wherein τ is the dosing interval.
 110. Thepharmaceutical composition according to claim 100, wherein thecomposition is in a form for administration in an amount resulting in anarea under the concentration curve, AUC_(0-τ), of eslicarbazepinegreater than about 110,000 ng·h/ml, wherein τ is the dosing interval.111. The pharmaceutical composition according to claim 110, wherein thecomposition is in a form for administration in an amount resulting in aAUC_(0-τ) of eslicarbazepine greater than about 240,000 ng·h/ml. 112.The pharmaceutical composition according to claim 111, wherein thecomposition is in a form for administration in an amount resulting in aAUC_(0-τ) of eslicarbazepine greater than about 375,000 ng·h/ml. 113.The pharmaceutical composition according to claim 112, wherein thecomposition is in a form for administration in an amount resulting in aAUC_(0-τ) of eslicarbazepine greater than about 595,000 ng·h/ml. 114.The pharmaceutical composition according to claim 113, wherein thecomposition is in a form for administration in an amount resulting in aAUC_(0-τ) of eslicarbazepine greater than about 790,000 ng·h/ml. 115.The pharmaceutical composition according to claim 100, wherein thecomposition comprises at least about 400 mg of eslicarbazepine acetate.116. The pharmaceutical composition according to claim 115, wherein thecomposition comprises at least about 800 mg of eslicarbazepine acetate.117. The pharmaceutical composition according to claim 116, wherein thecomposition comprises at least about 1200 mg of eslicarbazepine acetate.118. The pharmaceutical composition according to claim 115, wherein thecomposition comprises an amount of eslicarbazepine acetate ranging fromabout 800 mg to about 2400 mg.
 119. The pharmaceutical compositionaccording to claim 115, wherein the composition comprises an amount ofeslicarbazepine acetate ranging from about 800 mg to about 1200 mg. 120.The pharmaceutical composition according to claim 115, wherein thecomposition comprises an amount of eslicarbazepine acetate ranging fromabout 400 mg to about 1200 mg.
 121. The pharmaceutical compositionaccording to claim 100, wherein the active ingredient in thepharmaceutical composition consists essentially of eslicarbazepineacetate.
 122. The pharmaceutical composition according to claim 100,wherein the composition comprising eslicarbazepine acetate isadministered as adjunctive therapy to a patient being treated with atleast one other anti-epileptic drug.
 123. The pharmaceutical compositionaccording to claim 122, where the serum concentration of the at leastone other anti-epileptic drug is not significantly decreased by theonce-daily dose of the pharmaceutical composition comprisingeslicarbazepine acetate.
 124. The pharmaceutical composition accordingto claim 122, wherein the at least one other anti-epileptic drug ischosen from valproate, lamotrigine, topiramate, and combinationsthereof.
 125. The pharmaceutical composition according to claim 100,wherein the pharmaceutical composition is in the form of a tablet or anoral suspension.
 126. The pharmaceutical composition according to claim125, wherein the oral suspension comprises at least one excipient,auxiliary substance or carrier material.
 127. The pharmaceuticalcomposition according to claim 126, wherein the at least one excipient,auxiliary substance or carrier material is selected from the groupconsisting of xanthan gum, macrogol stearate, methylparaben,propylparaben, saccharin sodium, sorbitol, buffers, flavourings andcombinations thereof.
 128. The pharmaceutical composition according toclaim 100, wherein the epilepsy is refractory partial epilepsy.
 129. Thepharmaceutical composition according to claim 100, wherein uponadministration of the pharmaceutical composition, the number, duration,or frequency of epileptic seizures in a patient decreases relative tothe number, duration or frequency of epileptic seizures in a patientwithout treatment.
 130. The pharmaceutical composition according toclaim 100, wherein upon administration of the pharmaceuticalcomposition, the frequency of epileptic seizures is reduced by 50% ormore.
 131. The pharmaceutical composition according to claim 100,wherein upon administration of the pharmaceutical composition patientsbecome seizure-free relative to a patient without treatment.
 132. Thepharmaceutical composition according to claim 100, wherein the patientis an adult.
 133. The pharmaceutical composition according to claim 100,wherein the patient is aged 18 to 65 years.
 134. The pharmaceuticalcomposition according to claim 100, wherein the pharmaceuticalcomposition is administered orally.
 135. A method for treating a patientwith partial-onset seizures, comprising: administering to the patient aonce-daily dose of a pharmaceutical composition comprisingeslicarbazepine acetate in a pharmacologically effective amount. 136.The method according to claim 135, wherein the once-daily dose isadministered in an amount resulting in a maximum observed plasmaconcentration, C_(max), of eslicarbazepine greater than about 7,400ng/mL.
 137. The method according to claim 136, wherein the once-dailydose is administered in an amount resulting in a C_(max) ofeslicarbazepine greater than about 12,000 ng/mL.
 138. The methodaccording to claim 135, wherein the once-daily dose is administered inan amount resulting in a maximum observed plasma concentration, C_(max),of eslicarbazepine up to about 58,800 ng/mL.
 139. The method accordingto claim 137, wherein the once-daily dose is administered in an amountresulting in a C_(max) of eslicarbazepine greater than about 22,700ng/mL.
 140. The method according to claim 139, wherein the once-dailydose is administered in an amount resulting in a C_(max) ofeslicarbazepine greater than about 36,500 ng/mL.
 141. The methodaccording to claim 140, wherein the once-daily dose is administered inan amount resulting in a C_(max) of eslicarbazepine greater than about45,200 ng/mL.
 142. The method according to claim 135, wherein theonce-daily dose is administered in an amount resulting in a maximumobserved plasma concentration, C_(max), of eslicarbazepine up to about67,800 ng/mL.
 143. The method according to claim 135, wherein theonce-daily dose is administered in an amount resulting in an area underthe concentration curve, AUC_(0-τ), of eslicarbazepine up to about885,000 ng·h/mL, wherein τ is the dosing interval.
 144. The methodaccording to claim 135, wherein the once-daily dose is administered inan amount resulting in an area under the concentration curve, AUC_(0-τ),of eslicarbazepine up to about 1,000,000 ng·h/mL, wherein τ is thedosing interval.
 145. The method according to claim 135, wherein theonce-daily dose is administered in an amount resulting in an area underthe concentration curve, AUC_(0-τ), of eslicarbazepine greater thanabout 110,000 ng·h/mL, wherein τ is the dosing interval.
 146. The methodaccording to claim 145, wherein the once-daily dose is administered inan amount resulting in a AUC_(0-τ) of eslicarbazepine greater than about240,000 ng·h/mL.
 147. The method according to claim 146, wherein theonce-daily dose is administered in an amount resulting in a AUC_(0-τ) ofeslicarbazepine greater than about 375,000 ng·h/mL.
 148. The methodaccording to claim 147, wherein the once-daily dose is administered inan amount resulting in a AUC_(0-τ) of eslicarbazepine greater than about595,000 ng·h/mL.
 149. The method according to claim 148, wherein theonce-daily dose is administered in an amount resulting in a AUC_(0-τ) ofeslicarbazepine greater than about 790,000 ng·h/mL.
 150. The methodaccording to claim 135, wherein the once-daily dose is administered in adosage comprising at least about 400 mg of eslicarbazepine acetate. 151.The method according to claim 150, wherein the once-daily dose isadministered in a dosage comprising at least about 800 mg ofeslicarbazepine acetate.
 152. The method according to claim 151, whereinthe once-daily dose is administered in a dosage comprising at leastabout 1200 mg of eslicarbazepine acetate.
 153. The method according toclaim 150, wherein the once-daily dose is administered in a dosagecomprising an amount of eslicarbazepine acetate ranging from about 800mg to about 2400 mg.
 154. The method according to claim 150, wherein theonce-daily dose is administered in a dosage comprising an amount ofeslicarbazepine acetate ranging from about 800 mg to about 1200 mg. 155.The method according to claim 150, wherein the once-daily dose isadministered in a dosage comprising an amount of eslicarbazepine acetateranging from about 400 mg to about 1200 mg.
 156. The method according toclaim 135, wherein the active ingredient in the pharmaceuticalcomposition consists essentially of eslicarbazepine acetate.
 157. Themethod according to claim 135, wherein the once-daily dose of thepharmaceutical composition comprising eslicarbazepine acetate isadministered as adjunctive therapy to a patient being treated with atleast one other anti-epileptic drug.
 158. The method according to claim157, where the serum concentration of the at least one otheranti-epileptic drug is not significantly decreased by the once-dailydose of the pharmaceutical composition comprising eslicarbazepineacetate.
 159. The method according to claim 157, wherein the at leastone other anti-epileptic drug is chosen from valproate, lamotrigine,topiramate, and combinations thereof.
 160. The method according to claim135, wherein the pharmaceutical composition is administered in the formof a tablet or an oral suspension.
 161. The method according to claim160, wherein the oral suspension comprises at least one excipient,auxiliary substance or carrier material.
 162. The method according toclaim 161, wherein the at least one excipient, auxiliary substance orcarrier material is selected from the group consisting of xanthan gum,macrogol stearate, methylparaben, propylparaben, saccharin sodium,sorbitol, buffers, flavourings and combinations thereof.
 163. The methodaccording to claim 135, wherein upon administration of thepharmaceutical composition, the number, duration, or frequency ofseizures in a patient decreases relative to the number, duration orfrequency of seizures in a patient without treatment.
 164. The methodaccording to claim 135, wherein the frequency of seizures is reduced by50% or more.
 165. The method according to claim 135, wherein uponadministration of the pharmaceutical composition patients becomeseizure-free relative to a patient without treatment.
 166. The methodaccording to claim 135, wherein the patient is an adult.
 167. The methodaccording to claim 135, wherein the patient is aged 18 to 65 years. 168.The method according to claim 135, wherein the pharmaceuticalcomposition is administered orally.
 169. The method according to claim30, wherein the once-daily dose is administered in a dosage comprisingabout 200 mg of eslicarbazepine acetate.
 170. The method according toclaim 43, wherein the once-daily dose is administered in a dosagecomprising about 200 mg of eslicarbazepine acetate.
 171. Thepharmaceutical composition according to claim 100, wherein thecomposition comprises about 200 mg of eslicarbazepine acetate.
 172. Themethod according to claim 135, wherein the once-daily dose isadministered in a dosage comprising about 200 mg of eslicarbazepineacetate.
 173. The method according to claim 30, wherein the once-dailydose is administered in a dosage comprising about 400 mg ofeslicarbazepine acetate.
 174. The method according to claim 43, whereinthe once-daily dose is administered in a dosage comprising about 400 mgof eslicarbazepine acetate.
 175. The pharmaceutical compositionaccording to claim 100, wherein the composition comprises about 400 mgeslicarbazepine acetate.
 176. The method according to claim 135, whereinthe once-daily dose is administered in a dosage comprising about 400 mgof eslicarbazepine acetate.
 177. The method according to claim 30,wherein the once-daily dose is administered in a dosage comprising about600 mg of eslicarbazepine acetate.
 178. The method according to claim43, wherein the once-daily dose is administered in a dosage comprisingabout 600 mg of eslicarbazepine acetate.
 179. The pharmaceuticalcomposition according to claim 100, wherein the composition comprisesabout 600 mg eslicarbazepine acetate.
 180. The method according to claim135, wherein the once-daily dose is administered in a dosage comprisingabout 600 mg of eslicarbazepine acetate.
 181. The method according toclaim 30, wherein the once-daily dose is administered in a dosagecomprising about 800 mg of eslicarbazepine acetate.
 182. The methodaccording to claim 43, wherein the once-daily dose is administered in adosage comprising about 800 mg of eslicarbazepine acetate.
 183. Thepharmaceutical composition according to claim 100, wherein thecomposition comprises about 800 mg eslicarbazepine acetate.
 184. Themethod according to claim 135, wherein the once-daily dose isadministered in a dosage comprising about 800 mg of eslicarbazepineacetate.
 185. The method according to claim 30, wherein the once-dailydose is administered in a dosage comprising about 1200 mg ofeslicarbazepine acetate.
 186. The method according to claim 43, whereinthe once-daily dose is administered in a dosage comprising about 1200 mgof eslicarbazepine acetate.
 187. The pharmaceutical compositionaccording to claim 100, wherein the composition comprises about 1200 mgeslicarbazepine acetate.
 189. The method according to claim 135, whereinthe once-daily dose is administered in a dosage comprising about 1200 mgof eslicarbazepine acetate.
 190. The method according to claim 30,wherein the once-daily dose is administered in an initial dosagecomprising about 400 mg of eslicarbazepine acetate and increased atweekly intervals to a dosage of about 800 mg.
 191. The method accordingto claim 190, wherein the once-daily dose is further increased at weeklyintervals to a dosage of about 1200 mg.
 192. The method according toclaim 43, wherein the once-daily dose is administered in an initialdosage comprising about 400 mg of eslicarbazepine acetate and increasedat weekly intervals to a dosage of about 800 mg.
 193. The methodaccording to claim 192, wherein the once-daily dose is further increasedat weekly intervals to a dosage of about 1200 mg.
 194. The methodaccording to claim 135, wherein the once-daily dose is administered inan initial dosage comprising about 400 mg of eslicarbazepine acetate andincreased at weekly intervals to a dosage of about 800 mg.
 195. Themethod according to claim 194, wherein the once-daily dose is furtherincreased at weekly intervals to a dosage of about 1200 mg.
 196. Themethod according to according to claim 30, wherein the once-daily doseis administered in an amount resulting in a maximum plasmaconcentration, C_(max), of eslicarbazepine greater than about 22,700ng/mL and up to about 36,500 ng/mL.
 197. The method according to claim43, wherein the once-daily dose is administered in an amount resultingin a maximum plasma concentration, C_(max), of eslicarbazepine greaterthan about 22,700 ng/mL and up to about 36,500 ng/mL.
 198. Thepharmaceutical composition according to claim 100, wherein thecomposition is in a form for administration in an amount resulting in amaximum plasma concentration, C_(max), of eslicarbazepine greater thanabout 22,700 ng/mL and up to about 36,500 ng/mL.
 199. The methodaccording to claim 135 wherein the once-daily dose is administered in anamount resulting in a maximum plasma concentration, C_(max), ofeslicarbazepine greater than about 22,700 ng/mL and up to about 36,500ng/mL.
 200. The method according to according to claim 30, wherein theonce-daily dose is administered in an amount resulting in an area underthe concentration curve, AUC_(0-τ), of eslicarbazepine greater thanabout 375,000 ng·h/mL and up to about 595,000 000 ng·h/mL, wherein τ isthe dosing interval.
 201. The method according to claim 43, wherein theonce-daily dose is administered in an amount resulting in an area underthe concentration curve, AUC_(0-τ), of eslicarbazepine greater thanabout 375,000 ng·h/mL and up to about 595,000 000 ng·h/mL, wherein τ isthe dosing interval.
 202. The pharmaceutical composition according toclaim 100, wherein the composition is in a form for administration in anamount resulting in an area under the concentration curve, AUC_(0-τ), ofeslicarbazepine greater than about 375,000 ng·h/mL and up to about595,000 000 ng·h/mL, wherein τ is the dosing interval.
 203. The methodaccording to claim 135, wherein the once-daily dose is administered inan amount resulting in an area under the concentration curve, AUC_(0-τ),of eslicarbazepine greater than about 375,000 ng·h/mL and up to about595,000 000 ng·h/mL, wherein τ is the dosing interval.